Poly(urea-urethane) compositions useful as topical medicaments and methods of using the same

ABSTRACT

The present invention provides a method of treating a skin ailment including administering to a subject in need thereof, a therapeutically effective amount of a composition including (i) a primary diamine; (ii) a secondary aromatic diamine; (iii) a polyisocyanate; and (iv) optionally, a polyol. The present invention also provides a method of forming a skin bandage.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. Provisional Application Ser.Nos. 60/979,573 filed Oct. 12, 2007 and 61/022,059 filed Jan. 18, 2008,the disclosures of which are hereby incorporated by reference herein intheir entireties.

FIELD OF THE INVENTION

The present invention relates to topical medicaments for treating skinailments. The present invention also relates to the topical medicamentsfor treating bacterial, viral and fungal infections. The presentinvention also relates to methods of treating skin ailments, to methodsof forming poly(urea-urethane) skin bandages, and to methods of treatingbacterial, viral and fungal infections.

BACKGROUND OF THE INVENTION

Skin is the largest organ of the human body and is responsible for anumber of bodily functions, including protection, temperatureregulation, absorption and excretion necessary for bodily regulation,etc. Skin aliments or disorders, however, may retard the skin's functionand may limit its ability to protect the body. Moreover, skin ailmentsmay cause irritation, discomfort and/or pain to an inflicted individual.

Examples of skin ailments include rashes, including those caused bycontact with rash-causing source, such as poison sumac, poison oak,poison ivy; bites or stings, such as from bees, yellow jackets, wasps,spiders, mosquitoes, cats and dogs; burns, such as first or seconddegree burns; sunburn; rosacea; sores, such as bed sores and Herpessores; Kaposi's sarcoma and other skin ailments associate with HIVand/or AIDS; scarring, such as from surgery or via keloid scarring;warts, such as plantar warts; hemorrhoids; anal sphincter muscle tears;and cuts and scrapes, and the like.

There remains a need in the art for compositions that are effective intreating these and other ailments, ameliorating their symptoms, such aspain, discomfort and/or swelling, and reducing or preventing infection.Furthermore, it would be desirable for such compositions to be availableas “one pot” or “single component” formulations. It would also bedesirable for such compositions to be useful for more than one of theseskin ailments, so as to be a multi-purpose medicament for various skinailments.

There also remains a need in the art for compositions that can be usedto treat viral, bacterial and fungal infections of the skin. Such skininfections may result from other skin ailments, or the skin infectionsmay occur independently of any other skin ailment. Environments such ashospitals and nursing and retirement homes may have a relatively highrisk for developing and transmitting antibiotic resistant bacteria.Compositions that can be used to treat antibiotic resistant bacteriawould therefore be particularly desirable for use in these environments.

SUMMARY OF THE INVENTION

The present invention provides a method of treating a skin ailmentcomprising administering to a subject in need thereof, a therapeuticallyeffective amount of a composition comprising (i) a primary polyamine;(ii) a polyisocyanate; and (iii) optionally, a polyol. The presentinvention also provides a method of forming a skin bandage comprisingproviding a composition comprising (i) a primary polyamine, (ii) apolyisocyanate, and (iii) optionally, a polyol, to a portion of skin ofa subject; and allowing the composition to cure on the skin of thesubject.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph illustrating the release of formulchon comprisingExample 1 and a hydrocortisone medicament through a nylon membrane.

FIG. 2 is a graph illustrating the release rate of a formulationcomprising Example 1 and hydrocortisone medicament.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The invention is described more fully hereinafter. This invention may,however, be embodied in many different forms and should not be construedas limited to the embodiments set forth herein. Rather, theseembodiments are provided so that this disclosure will be thorough andcomplete, and will fully convey the scope of the invention to thoseskilled in the art.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the term “and/or” includes any and all combinations of oneor more of the associated listed items. As used herein, the singularforms “a”, “an,” and “the” are intended to include the plural forms aswell, unless the context clearly indicates otherwise. It will be furtherunderstood that the terms “comprises” and/or “comprising,” when used inthis specification, specify the presence of stated features, integers,steps, operations, elements, and/or components, but do not preclude thepresence or addition of one or more other features, integers, steps,operations, elements, components, and/or groups thereof.

Unless otherwise defined, all terms (including technical and scientificterms) used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which this invention belongs. It will befurther understood that terms, such as those defined in commonly useddictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the relevant art andwill not be interpreted in an idealized or overly formal sense unlessexpressly so defined herein. All patents, patent applications andpublications referred to herein are incorporated by reference in theirentirety. In case of a conflict in terminology, the presentspecification is controlling.

Provided herein according to embodiments of the invention arepoly(urea-urethane) polymers that may be useful in treating particularskin ailments and/or protecting skin. Also provided herein arepharmaceutical compositions that may include a poly(urea-urethane)polymer according to an embodiment of the invention. Furthermore,provided herein are methods of using a poly(urea-urethane) polymerand/or a pharmaceutical composition according to an embodiment of theinvention to treat skin ailments and/or skin infection. Finally, methodsof forming a skin bandage using a poly(urea-urethane) polymer and/or apharmaceutical composition according to an embodiment of the inventionare also provided herein.

I. Definitions

As used herein, the following terms have the meanings provided below:

The term “alkyl” refers to a straight, branched or cyclic hydrocarbon.Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,n-decyl, and the like. “Lower alkyl” is a subset of alkyl and refers toa hydrocarbon group containing from 1 to 4 carbon atoms. Representativeexamples of lower alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like. Theterm “alkyl” is intended to include both substituted and unsubstitutedalkyl unless otherwise indicated. Substituted alkyl may be substitutedwith one or more (e.g., one, two or three) suitable functional groupsincluding, e.g., halo, alkyl, alkoxy, haloalkyl, amino, hydroxyl, aryl,isocyanato, and the like.

The term “alkoxy” refers to the functional group —OR, wherein R is analkyl, as defined herein.

The terms “aryl” and “arylene” refer to a monovalent or divalent,respectively, monocyclic carbocyclic ring system or a bicycliccarbocyclic fused ring system having one or more aromatic rings.Representative examples of aryl(ene) include, azulenyl(ene),indanyl(ene), indenyl(ene), naphthyl(idene), phenyl(ene),tetrahydronaphthyl(idene), and the like. The term “aryl(ene)” isintended to include both substituted and unsubstituted aryl unlessotherwise indicated. Substituted aryl(ene) may be substituted with oneor more suitable functional groups (e.g., one, two or three), including,e.g., alkyl and those groups set forth in connection with alkyl above.

The term “poly(urea-urethane) polymer” is meant to refer to (i)poly(urea) polymers and (ii) polymers that include both urea(—NRC(═O)NR′—) and urethane (—NR″C(═O)O—) linkages, wherein R, R′ and R″are each independently hydrogen; alkyl, as defined above; or aryl, asdefined above. All polymers herein are described according to themonomer units that react to form the polymer, such as, e.g., polyamines,polyols, polyisocyanates, and the like. The term “polymer” will beunderstood to include polymers, copolymers (e.g., polymers formed usingtwo or more different monomoers), oligomers and combinations thereof, aswell as polymers, oligomers, or copolymers that can be formed in amiscible blend. The term “pre-polymer” refers to a monomer or system ofmonomers that have been reacted to an intermediate molecular weightstate. This material is capable of further polymerization by reactivegroups to a fully cured high molecular weight state. As such, mixturesof reactive polymers with unreacted monomers may also be referred to aspre-polymers. Typically such prepolymers are polymers of relatively lowmolecular weight, usually between that of the monomer and the filmpolymer or resin. As such, one of skill in the art will appreciate thatmonomers react to form the poly(urea-urethane) such that the monomer isno longer present once the polymer is formed. However, in somepharmaceutical compositions described herein, both monomer and polymermay be present in the formulation prior to curing, and after curing,residual monomer may remain in the cured polymer.

The term “polyamine” is meant to refer to compounds having at least two(primary and/or secondary) amine functional groups per molecule.

The term “polyol” is meant to refer to compounds having at least twohydroxyl functional groups per molecule.

The term “polyisocyanate” and “polyisothiocyanate,” collectivelyreferred to as “polyiso(thio)cyanate” are meant to refer to compoundshaving at least two isocyanate or isothiocyanate, respectively,functional groups per molecule.

The terms “pharmaceutical composition” and “medicament” are usedinterchangeably herein to refer to a composition comprising atherapeutically effective amount of (i) a poly(urea-urethane) polymeraccording to an embodiment of the present invention, a pharmaceuticallyacceptable salt thereof and/or monomers thereof; (ii) a pharmaceuticallyacceptable carrier; and (iii) optionally, other additives.

The term “pharmaceutically acceptable salt” refers to a salt or saltsprepared from at least one pharmaceutically acceptable non-toxic acid orbase including inorganic acids and bases, and organic acids and bases.Pharmaceutically acceptable salts of compounds according to embodimentsof the invention include the acid addition and base salts thereof, andmay be made using techniques known in the art, such as, but not limitedto, reacting the compound with the desired base or acid. Suitablepharmaceutically acceptable base addition salts for compounds accordingto embodiments of the present invention include metallic salts (e.g.,alkali metal salts and/or alkaline earth metal salts) made fromaluminum, calcium, lithium, magnesium, potassium, sodium, and zinc; ororganic salts made from lysine, N,N′-dibenzylethyl-enediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine. Suitable non-toxic acids include, butare not limited to, inorganic and organic acids such as acetic, alginic,anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic,glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonicacid. Specific non-toxic acids include hydrochloric, hydrobromic,phosphoric, sulfuric, and methanesulfonic acids. Examples of specificsalts thus include xinofoate, hydrochloride mesylate, zinc, potassium,or iron salts. In certain embodiments, both water-soluble andwater-insoluble salts will be useful based on the mode ofadministration.

The term “pharmaceutically acceptable carrier” is used herein to referto a carrier medium that does not significantly alter the biologicalactivity of the poly(urea-urethane) polymer. The one or more substancesof which the pharmaceutically acceptable carrier is comprised typicallydepends on factors (or desired features for its intended use) of thepharmaceutical composition such as the intended mode of administration,desired physical state (e.g., solid, liquid, gel, suspension, etc.),desired consistency, desired appearance, desired taste (if any), desiredpharmacokinetic properties once administered (e.g., solubility,stability, biological half life), desired release characteristics (e.g.,(a) immediate release (e.g., fast-dissolving, fast-disintegrating), or(b) modified release (e.g., delayed release, sustained release,controlled release)), and the like. As known to those skilled in theart, a suitable pharmaceutically acceptable carrier may comprise one orsubstances, including but not limited to, a diluent, water, bufferedwater, saline, 0.3% glycine, aqueous alcohol, isotonic aqueous buffer; awater-soluble polymer, glycerol, polyethylene glycol, glycerin, oil,salt (e.g., such as sodium, potassium, magnesium and ammonium),phosphonate, carbonate ester, fatty acid, saccharide, polysaccharide,stabilizing agent (e.g., glycoprotein, and the like for impartingenhanced stability, as necessary and suitable for manufacture and/ordistribution of the pharmaceutical composition), excipient, preservative(e.g., to increase shelf-life, as necessary and suitable for manufactureand distribution of the pharmaceutical composition), bulking agent(e.g., microcrystalline cellulose, and the like), suspending agent(e.g., alginic acid, sodium alginate, and the like), viscosity enhancer(e.g., methylcellulose), taste enhancer (e.g., sweetner, flavoringagent, taste-masking agent), binder (generally, to impart cohesivequality to a tablet or solid formulation; e.g., gelatin, natural and/orsynthetic gums, polyvinylpyrrolidone, polyethylene glycol, and thelike), extender, disintegrant (e.g., sodium starch glycolate, sodiumcarboxymethyl cellulose, starch, and the like), dispersant, coating(generally to impart a surface active agent to a tablet or solidformulation; e.g., polysorbate, talc, silicon dioxide, and the like),lubricant (e.g., magnesium stearate, calcium stearate, sodium laurylsulphate, and the like), or colorant. Other suitable additives includethose described elsewhere herein. As known to those skilled in the art,an active ingredient may be formulated into a pharmaceutical compositionusing methods and one or more pharmaceutically acceptable carriers wellknown in the art, taking the desired features of the pharmaceuticalcomposition, as described above, in mind during formulation. Dependingon such desired features, typically a pharmaceutical composition maycomprise from about 1% by weight to about 80% by weight ofpoly(urea-urethane), and from about 10% by weight to about 99% by weightof pharmaceutically acceptable carrier.

The term “therapeutically effective amount” refers to that amount of apoly(urea-urethane) polymer according to an embodiment the presentinvention that is sufficient to prevent, minimize or improve/ameliorateone or more symptoms of one or more of the ailments described herein.Improvement/amelioration may be indicated visually, e.g., reducedredness, via laboratory testing and/or may be indicated by reduceddiscomfort or irritation to the inflicted subject.

The terms “treat”, “treating” and “treatment” means preventing orameliorating one or more of the ailments described herein. Thus, theterms apply to prophylactic and/or therapeutic applications. The termsalso apply to the prevention or amelioration of one or more symptoms ofa particular ailment, including the prevention or amelioration of anyinfection related to the particular ailment.

The term “bacteria,” as used herein, includes any organism from theprokaryotic kingdom, including gram positive and gram negative bacteria.These organisms include genera such as, but not limited to,Agrobacterium, Anaerobacter, Aqualbacterium, Azorhizobium, Bacillus,Bradyrhizobium, Cryobacterium, Escherichia, Enterococcus,Heliobacterium, Klebsiella, Lactobacillus, Methanococcus,Methanothermobacter, Micrococcus, Mycobacterium, Oceanomonas,Pseudomonas, Rhizobium, Staphylococcus, Streptococcus, Streptomyces,Thermusaquaticus, Thermaerobacter, Thermobacillus, and the like.Exemplary bacteria include those described in United States PatentApplication Publication No. 2003/0068808.

The term “virus,” as used herein, includes any virus, includingdouble-stranded DNA viruses (e.g., Adenoviruses, Herpesviruses,Poxviruses), single-stranded (—O-sense DNA viruses (e.g., parvoviruses),double stranded RNA viruses (e.g., Reoviruses), single-stranded (+)senseRNA viruses (e.g, Picornaviruses, Togaviruses), single-stranded (−)senseRNA viruses (e.g., Orthomyxoviruses, Rhabdoviruses), single stranded(+)sense RNA having a DNA intermediate in the life-cycle (e.g,Retroviruses), and double stranded DNA with RNA intermediate (e.g.,Hepadnaviruses). Exemplary viruses include humanpapilloma virus, herpessimplex virus and poxvirus.

The term “fungus,” as used herein, includes any fungus or mold,including arbuscular mycorrhiza, conidiophores, chytridiomycota,blastocladiomycota, neocallimastigomycota, zygomycota and glomeromycota.The term also includes slime molds and water molds. Exemplary fungiinclude candida, malassezia furfur, Pityrisporum ovalae, and dennophytessuch as Trichophyton, Microsporum and Epidermophyton.

II. POLY(UREA-URETHANE) POLYMERS ACCORDING TO EMBODIMENTS OF THEINVENTION

According to some embodiments of the present invention, provided arepoly(urea-urethane) polymers that include (a) a primary and/or secondarypolyamine; (b) a polyiso(thio)cyanate and/or a derivative thereof; (c)optionally, a polyol; and (d) optionally, additional comonomers.

(a) Primary and Secondary Polyamines

In some embodiments of the present invention, the poly(urea-urethane)polymer includes an aliphatic primary and/or secondary polyamine. Theprimary and/or secondary polyamine may also include various otherfunctional groups within the polyamine, including polyether, polyester,polycarbonate and/or polypropylene linkages.

In some embodiments, the polyamine includes a primary diamine thatincludes at least one polyoxyalkylenediamine. For example, in someembodiments, the polyamine includes a diamine encompassed by Formula 1.

wherein R₁ and R₂ are each independently hydrogen or alkyl;n is 0 or a positive integer, such as 1, 2, 3 or 4; andx is a positive integer in a range of 1 to 100, and in some embodimentsis 1, 2, 3, 4, 5, 10, 50 or 100. Exemplary primarypolyoxyalkylenediamines include Jeffamine® D-2000 polyetheramine,manufactured by Huntsman Petrochemical Corporation and Poly-A® 27-2000,manufactured by Arch Chemicals.

In some embodiments, the polyamine includes an aliphatic secondarydiamine that includes an N-alkyl polyoxyalkylenediamine. For example, insome embodiments, the polyamine includes an aliphatic secondary amineencompassed by Formula 2.

wherein R₁ and R₂ are each independently hydrogen or alkyl;R₃ and R₄ are each independently alkyl or aryl;n is 0 or a positive integer, such as 1, 2, 3 or 4; andx is a positive integer in a range of 1 to 100, and in some embodimentsis 1, 2, 3, 4, 5, 10, 50 or 100.

In some embodiments of the invention, the primary and/or secondarypolyamine included in the poly(urea-urethane) may include an aryl(ene)functional group, such as phenyl(ene), naphthyl(idene) and the like. Theprimary and/or secondary polyamine may also include various otherfunctional groups, such as polyether, polyester, polycarbonate and/orpolypropylene linkages.

In some embodiments, the polyamine includes an aromatic primary diamine,such as a compound encompassed by Formula 3.

wherein a is a positive integer, such as 1, 2, 3, 4 or 5. In particularembodiments, the primary amine groups are each located on theirrespective phenyl rings at the para position.

In some embodiments, the polyamine includes an aromatic secondarydiamine, such as a compound encompassed by Formula 4.

wherein a is a positive integer such as 1, 2, 3, 4 or 5, and R and R′are each independently alkyl or aryl. In particular embodiments, thesecondary amine groups are each located on their respective phenyl ringsat the para position. Exemplary aromatic secondary diamines includeUnilink® 4200, manufactured by Dorf Ketal Chemicals.

As one of ordinary skill in the art will appreciate, mixtures ofdifferent types of polyamines may be used in some embodiments of theinvention, including mixtures of primary and secondary amines.

(b) Polyisocyanates/Polyisothiocyanates

According to some embodiments of the present invention, apolyiso(thio)cyanate is included in the poly(urea-urethane) polymer. Anysuitable polyiso(thio)cyanate may be included in the compositionincluding, for example, aliphatic polyisocyanates, aromaticpolyisocyanates, alicyclic polyisocyanates, heterocyclic polyisocyanatesand heteraromatic polyisocyanates. Exemplary polyisocyanates includepolyaryl polyisocyanates as defined in U.S. Pat. No. 2,683,730; tolylenediisocyanate (also referred to as “TDI”);triphenylmethane-4,4′4″-triisocyanate, benzene-1,3,5-triisocyanate;toluene-2,4,6-triisocyanate; diphenyl-2,4,4′-triisocyanate;hexamethylene diisocyanate; xylylene diisocyanate; chlorophenylenediisocyanate; diphenylmethane-4,4′-diisocyanate;naphthalene-1,5-diisocyanate; xylene-alpha, alpha′-diisothiocyanate;3,3′-dimethyl-4,4′biphenylene diisocyanate;3-3′dimethoxy-4,4′-biphenylene diisocyanate;2′,3,3′-dimethyl-4,4′-biphenylene diisocyanate;5,5′-tetramethyl-4,4′biphenylene diisocyanate;2,2′,5,5′-tetramethyl-4,4′biphenylene diisocyanate,4,4′methylenebis(phenylisocyanate); 4,4′-sulfonylbis(phenylisocyanate);4,4′-methylene di-orthotolylisocyanate; ethylene diisocyanate; ethylenediisothiocyanate; ethylidene diisocyanate; propylene diisocyanate;butylene diisocyanate; cyclopentylene-1,3-diisocyanate;cyclohexylene-1,4-diisocyanate; cyclohexylene-1,2.diisocyanate,2,4-tolylene diisocyanate; 2,6-tolylene diisocyanate;4,4′-diphenylmethane diisocyanate;2,2-diphenylpropane-4,4′-diisocyanate; p-phenylene diisocyanate;m-phenylene-1,5 diisocyanate; xylylene diisocyanate; 1,4-napthylenediisocyanate; 1,5-naphthylene diisocyanate; diphenyl-4,4′diisocyanate;azobenzene-4,4′-diisocyanate; diphenylsulfone-4,4′-diisocyanate;dichlorohexamethylene diisocyanate; tetramethylene diisocyanate;pentamethylene diisocyanate; hexamethylene diisocyanate;1-chlorobenzene-2,4-diisocyanate; furfurylidene diisocyanate; triphenylmethane triisocyanate; 1,4-tetramethylene diisocyanate;1,6-hexamethylene diisocyanate; 2,2,4-trimethyl-1.6-hexamethylenediisocyanate; 1,12-dodecamethylene diisocyanate; cyclohexane-1,3(and-1,4)-diisocyanate; 1-isocyanato-2-isocyanatomethyl cyclopentane;1-isocyanato-3-isocyanatomethyl-3,5,5-trimethyl-cyclohexane (isophoronediisocyanate or IPDI); bis-(4-isocyanatocyclohexyl)-methane;2,4′dicyclohexyl-methane diisocyanate; 1,3- and1,4-bis(isocyanatomethyl)-cyclohexane;bis-(4-isocyanato-3-methyl-cyclohexyl)-methane,α,α,α′,α′-tetramethyl-1,3-1-isocyanato-1-methyl-4(3)-isocyanatomethylcyclohexane; 2,4-, 1,3- and/or 1,4-phenylene diisocyanate; 2,4- and/or2,6-toluoylene diisocyanate; 2,4- and/or 4,4′-diphenyl-methanediisocyanate; 1,5-diisocyanato naphthalene; aromatic polyisocyanatescontaining 3 or more isocyanate groups such as 4,4′,4″-triphenylmethanediisocyanate, trimethylenediisocyanate, tetramethylene diisocyanate andhexamethylene diisocyanate; xylene diisocyanate; 1,5-napththylenediisocyanate; 1,4-phenylene diisocyanate; 4,4′-′diphenylmethanediisocyanate (also referred to as “MDI”) (Dow's ISONATE® 125M);4,4′4″-triphenylmethane triisocyanate; and3,3′-dimethyl-4.4′-diphenylmethane diisocyanate; and the like. Aliphaticdiisocyanates such as the C₃₆ aliphatic diisocyanate derived from thedimer of ricinoleic acid can also be suitably employed and arecommercially available, for example, as DD1-1410 (Henkel Corporation,Resin Division, Minneapolis. Minn.). Other examples of polyisocyanatescan be found, for example, in The Development and Use of PolyurethaneProducts, E. N. Doyle, McGraw-Hill Book Company, page 27 (1971) andPolyurethane Handbook, Gunter Oertel Hauser. Gardner Press (1994).

Mixtures of two or more polyiso(thio)cyanates may also be used.Furthermore, different isomers of the same isocyanate or isothiocyanatemay be used. For example, in some embodiments, a mixture (e.g., 80/20 or65/35 by weight) of 2,4-toluene diisocyanate and 2,6 toluenediisocyanate may be used.

In some embodiments of the invention, the polyiso(thio)cyanates areliquid at ambient temperatures. Liquid polyiso(thio)cyanates mayfacilitate the production of polymeric products and may obviate the needto melt or dissolve a polyiso(thio)cyanate prior to reacting it.Suitable liquid polyisocyanate materials are known to those of ordinaryskill in the art and include, e.g., a liquid polyisocyanate disclosed inU.S. Pat. No. 3,394,164.

Prepolymer polyisocynates of higher molecular weight (e.g., greater than500 grams per mole) that have been cleanly stripped of low molecularweight diisocynate starting materials may be particularly useful inapplications wherein the presence of trace diisocyanate monomers may beundesirable in end use applications, e.g., when trace diisocyanatemonomers may cause irritation or sensitization.

In particular embodiments of the invention, the polyisocyanate is MDI ora derivative thereof. MDI is a solid with a melting point of 38° C. andmay form significant quantities of insoluble dimers when stored above40° C. Therefore, so-called “modified” MDI derivatives, which are liquidat room temperature and have a reduced tendency to dimerize, may beused. Modified MDIs include those formed by reacting the diisocyanatewith a short polyol in a 2:1 diisocyanate to diol ratio, with a shorttriol in a 3:1 diisocyanate to triol ratio or by converting part of themixture to a trifunctional carbodiimide-based diisocyanate trimer havingthe structure of Formula 5. Such an admixture may be obtained from Dow(Liquid MDI, Isonate 143L).

Both of these modifications may provide the MDI with suitable reactivityand a relatively long shelf-life. In some cases, a modified MDI havingapproximately 2.2 isocyanate groups per molecule may have a shelf lifeof up to 6 months, in a moisture-controlled environment, and at atemperature of between 25° C. and 35° C.

The MDI may also include mixtures of different isomers, including 2,4and 2,2 isomers. The 2-substituted configuration is typically lessreactive than the 4-substituted configuration. The use of differentisomers may affect the polymer architecture of the poly(urea-urethane)polymer, and additionally, when a relatively high percentage of MDIisomers is incorporated into the poly(urea-urethane), a lower molecularweight polymer may result. Furthermore, 2,4- and 2,2-linkages mayintroduce a “kink” or bend in the polymer chain, which may reduce thetendency of the materials to crystallize. The choice of MDI derivative(e.g., isomer) may affect properties of the solution, the cured film(e.g., curing time), etc. Therefore, the composition of the MDI (or anypolyisocyanate/polyisothiocyanate) may be selected as desired for aparticular application.

Liquid polyisocyanates may also be formed during the synthesis of MDI.In the production of MDI via the condensation of aniline withformaldehyde, thereby converting the amine groups to the correspondingisocyanate groups, a portion of the initially formed bis-adduct ofaniline and formaldehyde may further react with the reaction mixture toform polymeric aniline derivatives that may be converted to isocyanates.Typically, such polymeric derivatives will have a functionality of fromabout 4 to about 15, and in some cases, about 10 isocyanate groups permolecule. Such polymeric polyiscocyanates may be obtained after removalof pure MDI by distillation. These polyisocyanate products may be usedby themselves or in an admixture with pure MDI. For example, theundistilled reaction mixture of pure MDI with the polymeric MDI may beused. Such polymeric MDI products are commercially available under suchtrade designations as RUBINATE® M, RUBINATE® LF-168 and RUBINATE® LF-209(Huntsman Polyurethanes, Geisman, La.) and PaPI 27, PaPI 135, PaPI 580and PaPI 901 (Dow, Kalamazoo, Mich.).

In some embodiments of the invention, the polyiso(thio)cyanate componentmay be present in the form of a polyiso(thio)cyanate adduct. Forexample, the polyisocyanate may be present as an adduct that includesisocyanurate, uretidone, biuret, urethane, allophanate, carbodiimideand/or oxadiazinetrione groups. In some embodiments, the polyisocyanateadducts have an average functionality of 2 to 6 and an NCO content of 5to 30% by weight. The isocyanato-isocyanurates generally have an averageNCO functionality of 3 to 3.5 and an NCO content of 5 to 30%, in someembodiments 10 to 25%, and in particular embodiments, 15 to 25% byweight. In some embodiments of the invention, a mixture ofpolyisocyanate adducts are present, such as a mixture of isocyanurateand allophanate groups.

According to some embodiments of the invention, the polyiso(thio)cyanatecomponent is present as a prepolymer (hereinafter, collectively referredto as “NCO prepolymer”). Such NCO prepolymers may be prepared from anyof the previously described polyiso(thio)cyanates and/orpolyiso(thio)cyanurate adducts, in combination with an organic compoundthat is capable of reacting with the polyiso(thio)cyanates and/orpolyiso(thio)cyanurate adducts. In some embodiments, such organiccompounds include a polyol, e.g., a polyol described herein. In someembodiments, the prepolymer is formed with an organic compound having anumber average molecular weight in a range of 400 to 6000, and in someembodiments, in a range of 800 to 3000. Furthermore, in someembodiments, the prepolymer is formed with an organic compound having anumber average molecular weight of less than 400. Such molecular weightsmay be determined by end group analysis (OH number).

With regard to the organic polyisocyanates, the prepolymers andpolyisocyanate adducts, reference is made to U.S. Pat. No. 5,516,873 andU.S. Pat. No. 6,515,125 and references contained therein.

As one of skill in the art would readily appreciate, mixtures of any ofthe above polyiso(thio)cyanates, including derivatives thereof, may beincorporated in the poly(urea-urethane) polymers described herein. Inparticular embodiments, mixtures of MDI and derivatives thereof areutilized, including those mixtures marketed under the tradenameLupranate® (e.g., Lupranate® 81 and 218), manufactured by BASFAktiengesellschaft.

(c) Polyols

In some embodiments of the invention, a polyol is not used to form thepoly(urea-urethane) polymer. In such a case, a poly(urea) may be formed.However, in some embodiments of the invention, a polyol may beincorporated into the polymer and a poly(urea-urethane) polymer may beformed. For example, in some embodiments, an aliphatic polyol isincluded in the poly(urea-urethane) polymer. In some embodiments, thealiphatic polyol includes a diol having a structure encompassed byFormula 5.

HO—(CH₂)_(n)—OH  Formula 5

wherein n is a positive integer. In some embodiments n is a positiveinteger in a range of 1 to 6, in some embodiments in a range of 5 to 9,and in some embodiments, n is 1, 2, 3 or 4. Exemplary polyols includeethylene glycol, propylene glycol and butylene glycol (such as 1,3-,1,4- and 2,3-butylene glycol).

In some embodiments, the polyol includes a diol having a structureencompassed by Formula 6.

wherein p is a positive integer, and R and R′ are each independentlyhydrogen or alkyl. In some embodiments, p is an integer in a range of 1to 100, in particular embodiments, p is 1, 2 or 3; and in particularembodiments p is 4 or more. Exemplary polyols include polyethyleneglycol and polypropylene glycol having various molecular weights (e.g.,200, 400, 600, 1000). Other polyols include trimethylol propane andthose marketed under the name Multranol® (e.g., Multranol® 4012),manufactured by Bayer Material Science.

As one of ordinary skill in the art will appreciate, mixtures of polyolsmay be used in some embodiments of the invention. In particularembodiments, ethylene glycol and propylene glycol are provided in equalamounts. Additionally, as described above, in particular embodiments,polyols may be used to form prepolymers with the polyiso(thio)cyanates.

(d) Additional Comonomers

In some embodiments of the invention, other comonomers may be reactedwith the polyamines, (optionally) polyols and poly(iso)thiocyanates andbecome incorporated into the poly(urea-urethane) polymer. For example,in some embodiments, siloxanes may be incorporated into thepoly(urea-urethane). Siloxane segments may impart additional waterresistance and flexibility to the coating. Additionally, siloxanes suchas poly(dimethyl siloxane) may be used to treat burns, and soincorporating such materials into the poly(urea-urethane) may provideadditional beneficial properties to the coatings. Such siloxane segmentsmay be introduced into the poly(urea-urethane) by incorporatingsiloxane-containing polyols, polyamines, polyisocyanates, alcohols,amines and isocyanates into the reaction mixture. Exemplary polyols andpolyamines may be found in U.S. Pat. Nos. 3,384,599, 4,737,558,4,962,178, 4,942,212, 5,221,724, 5,430,121, 5,589,563 and 5,196,458.

Fluorinated comonomers may also be included in the poly(urea-urethane)polymer, according to some embodiments of the invention. Fluorinatedsegments incorporated into the polyurea/urethane polymer may impartadditional water resistance/repellency, and may also impart hydrocarbonresistance and/or low surface tension materials, in embodiments whereinsuch characteristics are desirable. Such fluorinated segments may beintroduced into the poly(urea-urethane) by incorporatingfluorine-containing polyols, polyamines, polyisocyanates, alcohols,amines and isocyanates into the reaction mixture. Such fluorinatedcomonomers are known to those skilled in the art. Exemplary fluorinatedcomonomers include those described in U.S. Pat. No. 5,453,540, EP0646796B1 and WO 2007/011593A1.

(e) Synthesis of the Poly(Urea-Urethane) Polymers

The poly(urea-urethane) polymers according to embodiments of theinvention may be prepared using any suitable technique known to those ofskill in the art. As such, the polymerization methods may be homogenousor heterogeneous, including, e.g., solution, precipitation, suspensionand emulsion polymerization methods. Such polymerization techniques aredescribed in further detail in Principles In Polymerization, by GeorgeOdian (Wiley-Interscience, 4^(th) ed., 2004). Specific examples ofheterogeneous polymerizations including isocyanate-based polymerizationsto form polyureas and polyurethanes, and related polymers, may be foundin U.S. Pat. No. 4,107,256 and U.S. Pat. No. 6,197,878.

Depending on the polymerization method utilized, additional surfactantsor stabilizers may necessary in order to prevent agglomeration orprecipitation. Such additives are well-known to those of skill in theart and may be chosen so as to be chemically incorporated (e.g.,covalently linked) into the poly(urea-urethane) polymer. Such additivesmay also be chosen so as to avoid reactivity with the monomers employedin the formulation.

The order and rate of adding the polyamines, polyols, additionalmonomers and polyiso(thio)cyanates may substantially alter the finalarchitecture of the resulting prepolymer. As such, various preparationsmay be used to achieve the desired polymer structure. In someembodiments of the invention, the polyamine, polyol, polyisocyanate andadditional comonomers may be added to a solvent at one time, or may beadded in a particular order. Toward this end, in some embodiments, oneor more of the monomers may be added to the reaction mixture in acontinuous addition mode (e.g., via batch, semi-batch or continuouspolymerization methods). Additionally, under some circumstances,specific combinations of monomers, such as polyamines andpolyisocyanates, or polyols and polyisocyanates, may be reacted in afirst step to form a polymeric isocyanate prepolymer. Such prepolymersynthesis may allow for the further control of polymer architecture,solubility or allow for tailoring of the properties of the final polymersurface. In particular embodiments of the invention, all polyamine andpolyol monomers are added to a solvent in a first step and then theisocyanate is added in a second step. In such circumstances, theisocyanate will react and incorporate the polyamines and polyols in astatistical fashion according to their relative reactivity.

Catalysts may be added to the polymerization mixture in order toincrease or otherwise control polymerization or curing rates. Suchcatalysts are known to those of skill in the art, and include, e.g., thecatalysts described in U.S. Pat. No. 4,960,620. The polyamines andpolyols may react with the polyisocyanate at room temperature. However,in some embodiments, the reaction medium can be heated to facilitate thereaction.

III. PHARMACEUTICAL COMPOSITIONS ACCORDING TO EMBODIMENTS OF THEINVENTION

In some embodiments of the invention, provided are pharmaceuticalcompositions that include (a) at least one poly(urea-urethane) polymeraccording to an embodiment of the present invention, a pharmaceuticallyacceptable salt thereof and/or monomers thereof; (b) a pharmaceuticallyacceptable carrier; and (c) optionally, other additives.

Poly(Urea-Urethane) Polymers

Any of the polyurea or poly(urea-urethane) polymers described herein maybe included in pharmaceutical compositions according to embodiments ofthe invention. In addition, monomers that will form such polymers uponcuring may also be included in pharmaceutical compositions according toembodiments of the invention. Furthermore, mixtures of any polyureapolymer, poly(urea-urethane) polymer and monomers thereof may also bepresent in pharmaceutical compositions according to embodiments of theinvention.

(b) Pharmaceutically Acceptable Carrier/Solvent

According to some embodiments of the invention, pharmaceuticalpoly(urea/polyurethane) compositions include a pharmaceuticallyacceptable carrier. In some embodiments, the pharmaceutically acceptablecarrier is a solvent that can completely dissolve the monomers(polyamines and polyiso(thio)cyanates, and optionally, polyols andadditional comonomers). Additionally, in some embodiments, thepharmaceutically acceptable carrier will reduce the reaction between thereactive groups in the poly(urea-urethane) monomers and/or reduce orprevent the poly(urea-urethane) from solidifying or gelling until thedesired time, such as when the solvent is removed from the solution,e.g., via evaporation.

In particular embodiments of the invention, the pharmaceuticallyacceptable carrier includes a solvent such as an aldehyde; ketone;ester; ortho, meta, or para-dimethylbenzene; N-methylpyrrolidone;Solvesso solvent; a hydrocarbon solvent, such as a petroleum hydrocarbonsolvent; a lactone; a siloxane, or a mixture of any of the above.Additional solvents may be found in U.S. Patent Publication Nos.2006/021627, and U.S. Publication No. 2006/008856A1 and U.S. Pat. Nos.3,577,516, 4,987,893, 5,103,812, 6,458,376, 6,994,863, 5,874,481.

In some embodiments, an aldehyde or ketone solvent has a structureencompassed by Formula 7.

wherein R and R′ are each independently selected from hydrogen andalkyl. In some embodiments, the alkyl may include 1, 2, 3 or 4 carbonatoms. In some embodiments, R and R′ together form a ring, such as afive or six membered ring. Exemplary ketones include acetone,methylethylketone (MEK), methylisobutylketone and N-methylcyclohexanone.Exemplary aldehydes include acetaldehyde, propionaldehyde, butyraldehydeand isobutyraldehyde.

As an additional example, in some embodiments, an ester solvent has astructure encompassed by Formula 8.

wherein R is hydrogen, alkyl (such as an alkyl including 1, 2, 3 or 4carbon atoms) or alkoxy (such as an alkoxy that includes 1, 2, 3 or 4carbon atoms); and R′ is an alkyl group (such as an alkyl that includes1, 2, 3 or 4 carbon atoms). In some embodiments, R and R′ together forma ring, such as a ring that includes 2, 3, 4 or 5 carbon atoms.Exemplary ester solvents include methyl acetate, ethyl acetate, butylacetate, and methyl propyl acetate.

In particular embodiments of the invention, siloxane-based solvents,such as hexamethyldisiloxane, pentamer cyclomethicone tetramercyclomethicone and mixtures thereof can be employed inpoly(urea-urethane) compositions of the invention. Other suitablesiloxane solvents are described in U.S. Publication No. 2007/0041935 toSalamone et al., U.S. Pat. No. 6,280,752 to Panin, U.S. Pat. No.5,582,815 to Appino and U.S. Pat. No. 5,738,857 to Sejpka.

(c) Other Additives/Formulations

According to some embodiments of the invention, the compositionsdescribed herein may include other additives, including, but not limitedto, catalysts, UV absorbers, fillers, plasticizers, blowing agents,rheology modifiers, viscosity enhancers, adhesion promoters and thosedescribed in U.S. Patent Application Publication No. 2006/0216267. Otheradditives are described elsewhere herein.

In particular embodiments, formulations of the present invention aresuitable for topical administration for medical use and use in personalcare and/or hygiene (e.g., soaps, skin creams and/or lotions, soaps,cleansers, shampoos, wipes, towelettes, gels, etc.). In otherembodiments, the formulations exist in the form of a gel, emulsion,lotion or cream that can be readily used to treat the desired ailment.In still further embodiments, the formulations can be applied to theskin directly or to bandages for wound management.

In particular embodiments, topical compositions may include thepoly(urea-urethane) polymer, salts thereof and/or monomers thereof withvitamin E, vitamin A, conjugated linoleic acid, and essential fattyacids. The topical compositions disclosed herein are suitable fortopical application to mammalian skin. As described above, the carriercan be in a wide variety of forms, such as sprays, emulsions, mousses,liquids, creams, oils, lotions, ointments, gels and solids. In the caseof a solution, it can be lyophilized to a powder and then reconstitutedimmediately prior to use. For dispersions and suspensions, appropriatecarriers and additives include aqueous gums, celluloses, silicates oroils.

In particular embodiments, suitable pharmaceutically acceptable topicalcarriers include, but are not limited to, water, glycerol, alcohol,propylene glycol, fatty alcohols, triglycerides, fatty acid esters, andmineral oils. Suitable topical cosmetically acceptable carriers include,but are not limited to, solutions, emulsions, dispersions, suspensions,syrups, elixirs, and the like with suitable carriers and additives beingwater, alcohols, oils, glycols, preservatives, flavoring agents,coloring agents, suspending agents, petroleum jelly, petrolatum, mineraloil, vegetable oil, animal oil, organic and inorganic waxes, such asmicrocrystalline, paraffin and ozocerite wax, natural polymers, such asxanthanes, gelatin, cellulose, collagen, starch or gum arabic, syntheticpolymers, alcohols, polyols, and the like. Preferably, because of itsnon-toxic topical properties, the pharmaceutically and/orcosmetically-acceptable carrier is substantially miscible in water. Suchwater miscible carrier compositions can also include sustained ordelayed release carriers, such as liposomes, microsponges, microspheresor microcapsules, aqueous based ointments, water-in-oil or oil-in-wateremulsions, gels and the like.

In addition to liquids, the compositions according to embodiments of theinvention may be provided in an aerosol or non-aerosol spray. Theaerosol spray, whether formed from solid or liquid particles, can beproduced by the aerosol generator. Any suitable propellant may be usedin carrying out the present invention. Particularly, formulations to beapplied in spraying forms such as dispersible concentrates or powdersmay contain surfactants such as wetting and dispersing agents, e.g., thecondensation product of formaldehyde with naphthalene sulphonate, analkylarylsulphonate, a lignin sulphonate, a fatty alkyl sulphate, andethoxylated alkylphenol and an ethoxylated fatty alcohol.

In particular embodiments, formulations suitable for topical applicationto the skin can take the form of an ointment, cream, lotion, paste, gel,spray, aerosol, or oil. Carriers that can be used include petroleumjelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers,and combinations of two or more thereof.

Formulations suitable for rectal administration can be presented assuppositories. These can be prepared by admixing the compounds describedherein with one or more conventional excipients or carriers, forexample, cocoa butter, polyethylene glycol or a suppository wax, whichare solid at room temperature, but liquid at body temperature andtherefore melt in the rectum cavity and release the polymers andcompositions described herein.

(d) “Single Component” Formulations

According to some embodiments of the present invention, pharmaceuticalcompositions may be formulated as single component formulations. Theterm “single component,” as used herein, refers to a “one pot”formulation that does not require a curing agent or accelerant in orderto cure the formulation and form a film. Instead, the formulation can beadministered to a subject in need thereof in the manner in which it isstored, without combining or mixing the formulation with anothercomponent.

Such single component formulations may be obtained by reducing thereactivity of the components in the formulation. In order to achievethis, the single component formulations can be prepared by judiciousselection of the appropriate amounts of each component, as well as theappropriate amount and type of solvent. For example, in someembodiments, the solvent is present in the formulation in an amount in arange of about 10 weight percent and about 95 weight percent. Inparticular embodiments, the solvent is present in the formulation in anamount in a range of about 50 weight percent and about 90 weightpercent. Furthermore, in some embodiments, the polyamine componentincludes a secondary polyamine in an amount in a range of about 0.5weight percent and 5 weight percent. Additionally, the particularpolyiso(thio)cyanates included may also affect the reactivity and soparticular polyiso(thio)cyanates are useful for achieving singlecomponent formulations. For example, modified MDI polyisocyanates havinghigher percentages (e.g., in a range of 10% and 40%) 2-substitutedphenyl isocyanate groups, such as modified MDI polyisocyanates includingLupranate® 218 and Lupranate® 81, may be used.

In some embodiments, the amount of solvent employed is that which issufficient to dissolve a first set of reactants (polyamines andoptionally polyols and any additional comonomers) with thepolyiso(thio)cyanate second reactant, and allow for the reaction productthereof, i.e., the poly(urea-urethane) to remain in solution withoutprecipitation or gelling. Typically, the amount of solvent employed isabout 10 to 80% of the total reaction solution volume. The amount ofsolvent is adjusted depending upon the viscosity desired for specificapplication requirements. Typically, the reaction product viscosity willrange from about 0.05 centipoise to about 1800 centipoise at roomtemperature.

According to some embodiments of the invention, the single componentpoly(urea-urethane) compositions can be stored for a relatively longperiod of time, e.g. greater than 3 months at 25° C. without exhibitingprecipitation or gelling, greater than 6 months at 25° C. withoutprecipitation or gelling, or even greater than 1 year at 25° C. withoutprecipitation or gelling. Accordingly, such compositions can be appliedin any manner that allows for the removal of at least a portion of thepharmaceutically acceptable carrier, leading to the formation of asolid, cured poly(urea-urethane) material.

While the process and the single pot formulation permits the productionof polymeric materials without the use of blocking agents, end-cappingchemical modifications or thermally activated catalysts, e.g.caprolactum, B-carbonyl compounds (such as ethyl aceto acetate, ethylmalonate), alcohols and oximes; polymerization additives of varioustypes employed in the manufacture of polymeric products can desirably beemployed. For example, such polymerization agents as catalysts,ultraviolet absorbers, fillers, plasticizers, blowing agents, etc., canbe employed where desired. Further information on such additives may befound in U.S. Patent Publication No. 2006/0216267 and elsewhere herein.

III. METHODS OF USING POLY(UREA-URETHANE) POLYMERS AND PHARMACEUTICALCOMPOSITIONS ACCORDING TO EMBODIMENTS OF THE INVENTION

Provided herein, according to some embodiments of the invention, aremethods of treating particular skin ailments and infections. In someembodiments, the methods include administering to a subject apoly(urea-urethane) polymer according to an embodiment of the inventionto a subject. In some embodiments, methods include administering to asubject in need thereof, a therapeutically effective amount of apharmaceutical composition according to an embodiment of the invention.In particular embodiments, administering includes applying apoly(urea-urethane) or pharmaceutical composition according to anembodiment of the invention to the affected skin. Treatment of the skinailments and infections described herein may improve symptoms such aspain, discomfort, swelling, and/or infection. The particular skinailments and infections include those described herein.

In some embodiments of the invention, provided are methods of treatingrashes, include those caused by contact with rash-causing source, suchas poison sumac, poison oak, poison ivy.

In some embodiments of the invention, provided are methods of treatingbites or stings, such as from bees, yellow jackets, wasps, brownrecluse, spiders, mosquitoes, cats and dogs.

In some embodiments of the invention, provided are methods of treatingburns, for example, those being second degree or less, including sunburns.

In some embodiments of the invention, provided are methods of treatingrosacea.

In some embodiments of the invention, provided are methods of treatingsores, such as bedsores.

In some embodiments of the invention, provided are methods of treatingHerpes sores.

In some embodiments of the invention, provided are methods of treatingKaposi's sarcoma and other skin ailments associate with HIV and/or AIDS.

In some embodiments of the invention, provided are methods of treatingscarring, such as from surgery or keloid scarring.

In some embodiments of the invention, provided are methods of treatingwarts, such as plantar warts.

In some embodiments of the invention, provided are methods of treatinghemorrhoids and anal sphincter muscle tears.

In some embodiments of the invention, provided are methods of treatingcuts and scrapes.

In some embodiments of the invention, provided are methods of treating abacterial infection of the skin, in which the infection is caused orexacerbated by any type of bacteria. In some embodiments, the bacterialinfection is caused by or exacerbated by at least one of the followingbacteria: methicillin-susceptible, methicillin-resistant,vancomycin-susceptible and vancomycin-resistant staphylococci (includingStaphylococcus aureus, S. epidermidis, S. haemolyticus, S. hominis, S.saprophyticus, and coagulase-negative staphylococci), glycopeptideintermediaary-susceptible S. aureus (GISA), penicillin-susceptible andpenicillin-resistant streptococci (including Streptococcus pneumoniae,S. pyogenes, S. agalactiae, S. avium, S. bovis, S. lactis, S. sangiusand Streptococci Group C, Streptococci Group G and viridansstreptococci), enterococci (including vancomycin-susceptiple andvancomycin-resistant strains such as Enterococcus faecalis and E.faecium), Clostridium difficile, C. clostridiiforme, C. innocuum, C.perfringens, C. ramosum, Haemophilus influenzae, Listeria monocytogenes,Cornybacterium jeikeium, Bifidobacterium spp., Eubacterium aerofaciens,E. lentum, Lactobacillus acidophilus, L. casei, L. plantarum,Lactococcus spp., Leuconostoc spp., Pediococccus, Peptostreptococcusanaerobius, P. asaccorolyticus, P. magnus, P. micros, P. prevotii, P.productus, Propionibacterium acnes, Actinomyces spp., Moraxella spp.(including M. catarrhalis) and Escherichia spp. (including E. coli),mycobacterium (Mycobacterium tuburculosis, mycobacterium leprae,Mycobacterium avium complex, Mycobacterium avium subspeciesparatuberculosis, Mycobacterium palustre, Mycobacterium phlei,Mycobacteriaum smegmatis), Pseudomonas aeriginosa, micrococcus luteusand Serratia marcesens.

In some embodiments of the invention, the bacterial infection is treatedwith a composition according to an embodiment of the invention incombination with at least one other antibacterial, antiviral orantifungal agent. The at least one other antibacterial, antiviral orantifungal agent may be administered topically, or by any other route ofadministration (e.g, oral, via injection, etc.). Furthermore, thecomposition according to an embodiment of the invention and the at leastone other antibacterial, antiviral or antifungal agent may be usedsimulaneously or sequentially. Exemplary antibacterial agents include,but are not limited to, penicillins and related drugs, carbapenems,cephalosporins and related drugs, erythromycin, aminoglycosides,bacitracin, gramicidin, mupirocin, chloramphenicol, thiamphenicol,fusidate sodium, lincomycin, clindamycin, macrolides, novobiocin,polymyxins, rifamycins, spectinomysin, tetracyclines, vanomycin,teicoplanin, streptogramins, anti-folate agents including sulfonamides,trimethoprim and its combinations and pyrimethamine, syntheticantibacterials including nitrofurans, methenamine mandelate andmethenamine hippurate, nitroimidazoles, quinolones, fluoroquinolones,isoniazid, ethambutol, pyrazinamide, para-aminosalicylic acid (PAS),cycloserine, capreomycin, ethionamide, prothionamide, thiacetazone,viomycin, eveminomycin, glycopeptide, glyclyclycline, ketolides,oxazolidinone; imipenen, amikacin, netilmicin, fosfomycin, gentamycin,ceftriaxone, Ziracin, LY 333328, CL 331002, HMR 3647, Linezolid,Synercid, Aztreonam, and Metronidazole, Epiroprim, OCA-9983, GV-143253,Sanfetrinem sodium, CS-834, Biapenem, A-99058.1, A-165600, A-179796, KA159, Dynemicin A, DX8739, DU 6681, Cefluprenam, ER 35786, Cefoselis,Sanfetrinem celexetil, HGP-3 1, Cefpirome, HMR-3647, RU-59863,Mersacidin, KP 736, Rifalazil, Kosan, AM 1732, MEN 10700, Lenapenem, BO2502A, NE-1530, PR 39, K130, OPC 20000, OPC 2045, Veneprim, PD 138312,PD 140248, CP111905, Sulopenem, ritipenam acoxyl, RO-65-5788,Cyclothialidine, Sch-40832, SEP-132613, micacocidin A, SB-275833,SR-15402, SUN A0026, TOC 39, carumonam, Cefozopran, Cefetamet pivoxiland T 3811.

In some embodiments of the invention, provided are methods of treating aviral infection of the skin, in which the infection is caused orexacerbated by any type of virus.

In some embodiments, the infection is caused or exacerbated by at leastone the following viruses: humanpapilloma virus, herpes simplex virusand poxvirus. In some embodiments, the viral infection is treated with acomposition according to an embodiment of the invention in combinationwith at least one other antibacterial, antiviral or antifungal agent.The at least one other antibacterial, antiviral or antifungal agent maybe administered topically, or by any other route of administration (e.g,oral, via injection, etc.). Furthermore, the composition according to anembodiment of the invention and the at least one other antibacterial,antiviral or antifungal agent may be used simulaneously or sequentially.

In some embodiments of the invention, provided are methods of treating afungal infection of the skin, in which the infection is caused orexacerbated by any type of fungus. In particular embodiments, theinfection is caused or exacerbated by at least one of candida,malassezia furfur, pityrisporum ovalac, and dermophytes such asTrichophyton, Microsporum and Epidermophyton. In some embodiments of theinvention, the fungal infection is treated with a composition accordingto an embodiment of the invention in combination with at least one otherantibacterial agent, antiviral or antifungal agent. The at least oneother antibacterial, antiviral or antifungal agent may be administeredtopically, or by any other route of administration (e.g, oral, viainjection, etc.). Furthermore, the composition according to anembodiment of the invention and the at least one other antibacterial,antiviral or antifungal agent may be used simulaneously or sequentially.

In some embodiments of the invention, provided are methods of forming abandage on a portion of the skin of a subject. The methods includeproviding a composition according to an embodiment of the invention tothe skin; and allowing the composition to cure on the skin.

As one of skill in the art will understand, one or more skin ailments orinfections

(e.g., bacterial, viral and/or fungal) may be present at one time, andone or more compositions according to an embodiment of the invention,optionally in combination with at least one other antibacterial,antiviral or antifungal agent, may be used to treat one, some or all ofthe skin ailments and/or infections. In addition, in some embodiments, askin bandage formed by a method described herein may also act to treat askin ailment and/or infection of the skin in contact with the skinbandage.

Subjects suitable to be treated include, but are not limited to, avianand mammalian subjects. Mammals of the present invention include, butare not limited to, canines, felines, bovines, caprines, equines,ovines, porcines, rodents (e.g. rats and mice), lagomorphs, primates,humans, and the like, and mammals in utero. Any mammalian subject inneed of being treated according to the present invention is suitable.Human subjects are preferred. Human subjects of both genders and at anystage of development (i.e., neonate, infant, juvenile, adolescent,adult) can be treated according to the present invention.

Illustrative avians according to the present invention include chickens,ducks, turkeys, geese, quail, pheasant, ratites (e.g., ostrich) anddomesticated birds (e.g., parrots and canaries), and birds in ovo.

The invention can also be carried out on animal subjects, particularlymammalian subjects such as mice, rats, dogs, cats, livestock and horsesfor veterinary purposes, and for drug screening and drug developmentpurposes.

The amount of a composition to be applied, will depend on variousfactors such as the compound employed in the formulation, the purpose ofthe treatment (prophylactic or therapeutic), the type of ailment to betreated and the application time.

Any suitable method of administering a poly(urea-urethane) orpharmaceutical composition according to an embodiment of the inventionmay be used. In some embodiments, the poly(urea-urethane) orpharmaceutical composition may be applied topically to the skin. Forexample, the poly(urea-urethane) or pharmaceutical composition may bepresent in a liquid, cream, lotion, emulsion or other formulation, andthe such formulation may be placed directly on the skin, either via handapplication, via an applicator, via a spray or aerosol, or via any knownmethod of applying medicaments to the skin. For rectal tears, asuppository may be used to apply the polymers and compositions accordingto embodiments of the invention.

In some embodiments of the invention, pretreating skin or tissue priorto the application of a pharmaceutical composition according to anembodiment of the invention may be advantageous. For example, insituations (e.g., burn treatment) when strong adhesion of the polymerfilm to the tissue may be undesirable, pretreating the skin with acleaning solution that incorporates a low surface energy surfactantcapable of reacting with the residual isocyanate groups in thepoly(urea-urethane), may reduce the reaction of the isocyanate groupswith the tissue, thereby reducing adhesion. Conversely, in situationswhen strong adhesion of the poly(urea-urethane) may be desirable (suchas in wound closure/skin bandage), pretreating the skin with a cleaningsolution that removes compounds that are capable of reacting with theisocyanate functionalities in the poly(urea-urethane) may allow for theisocyanate functionalities to react with amine and hydroxylfunctionalities in the skin or tissue, thereby promoting adhesion.Additionally, compounds such as carboxylic acids (e.g., fatty acids)that are known to promote/catalyze isocyanate-based curing reactions canalso be used in pretreating and/or cleaning of the skin. Other compoundsthat may promote or provide control over adhesion of thepoly(urea-urethane) film when used in pretreatment include polymers ormonomers that include alcohol, amine or other nucleophilic groupscapable of reacting with isocyanate functionality. Examples of suchcompounds include poly(vinyl alcohol), poly(vinyl acetate), poly(vinylamine), poly(vinyl acetamide) and their copolymers.

In some embodiments, a particular poly(urea-urethane) or pharmaceuticalcomposition may be useful for more than one of the skin ailmentsdescribed above. Furthermore, in some embodiments, thepoly(urea-urethane) or pharmaceutical composition may be useful as botha polymeric skin bandage and a treatment for at least one of the skinailments described herein.

The present invention will now be described with reference to thefollowing examples. It should be appreciated that these examples are forthe purpose of illustrating aspects of the present invention, and do notlimit the scope of the invention as defined by the claims.

EXAMPLES

For each of the following examples, the reagents are added in the ordergiven with stirring for approximately 5 minutes in between reagentadditions. The MDI is added last and is added slowly with stirring. Thereactions were maintained at room temperature, ca. 70° C., throughoutthe reaction. After isocynate addition was complete, the reactions werestirred for approximately 10 minutes and then transferred to sample jarsfor storage prior to being characterized using a combination of HighPerformance Liquid Chromatography (HPLC), Gel Permeation Chromatography(GPC), Gel Permeation Chromatography with Multi Angle Light Scatteringdetection (GPC-MALS), Nuclear Magnetic resonance (NMR) Spectroscopy toFourier Transform Infra Red (FT-IR) Spectroscopy to determine molecularweight, verify chemical structure and verify reaction completion.

Example 1

Acetone  850 ml Methyl Ethyl Ketone  100 ml Polyetheramine; D-2000 60.0ml Secondary Diamine; UOP 4200 15.0 ml Polyether Polyol; Multranol 401220.0 ml Ethylene Glycol  5.0 ml Propylene Glycol  5.0 ml MDI Lupranate5143 32.0 ml

The resulting product was a clear, off white solution from which a smallamount of white solid precipitated and settled to the bottom of thereaction flask. FT-IR spectroscopy and NMR spectroscopy were used tovalidate structure and showed that only a small portion of isocynategroups are present in the reactive prepolymer. GPC characterizationresulted in polystyrene equivalent number average molecular weight of1,990 g/mol, weight average molecular weight of 6,910 g/mol andpolydispersity index of 3.5. No peaks corresponding to residual startingmaterial were observed in the chromatogram.

Example 2

Acetone 212.5 ml  Methyl Ethyl Ketone   25 ml Polyetheramine; D-200015.0 ml Secondary Diamine; UOP 4200 3.75 ml Polyether Polyol; Multanol4012  5.0 ml Ethylene Glycol 1.25 ml Propylene Glycol 1.25 ml MDI;Lupranate 81  8.0 ml

The resulting product was a clear, off white solution from which a smallamount of white solid precipitated and settled to the bottom of thereaction flask. FT-IR spectroscopy and NMR spectroscopy were used tovalidate structure and showed that only a small portion of isocyanategroups are present in the reactive prepolymer. GPC characterizationresulted in polystyrene equivalent number average molecular weight of1,960 g/mol, weight average molecular weight of 9120 g/mol andpolydispersity index of 4.6. No peaks corresponding to residual startingmaterial were observed in the chromatogram.

Example 3 Additional

Acetone 212.5 ml  Methyl Ethyl Ketone   25 ml Polyetheramine; D-200015.0 ml Secondary Diamine; UOP 4200 3.75 ml Polyether Polyol; Multanol4012  5.0 ml Ethylene Glycol 1.25 ml Propylene Glycol 1.25 ml MDI;Lupranate 81  8.0 ml

The resulting product was a clear, off white solution from which a smallamount of white solid precipitated formed and settled to the bottom ofthe reaction flask. FT-IR spectroscopy and NMR spectroscopy were used tovalidate structure and showed that only a small portion of isocynategroups are present in the reactive prepolymer. GPC characterizationresulted in polystyrene equivalent number average molecular weight of1,740 g/mol, weight average molecular weight of 3,110 g/mol andpolydispersity index (M_(w)/M_(n)) of 1.8. No peaks corresponding toresidual starting material were observed in the chromatogram.

Example 4

In this example, the polyetheramine, D-2000, was first dissolved in amixture of 400 ml acetone and 50 ml Methyl ethyl ketone. The MDI,Lupranate 5143, 32.0 ml was then added slowly in order to form apolyether amine prepolymer adduct. The remaining acetone and Methy Ethylketone are placed in a second reaction flask and the remaining reagentsadded in turn with stirring. Once the remaining co-monomers were alldissolved the polyetheramine/MDI prepolymer aduct was added slowly tothe second reaction flask. The resulting formulation was clear with aslightly yellow tint.

Acetone  850 ml Methyl Ethyl Ketone  100 ml Polyetheramine; D-2000 60.0ml Secondary Diamine; UOP 4200 15.0 ml Polyether Polyol; Multranol 401220.0 ml Ethylene Glycol  5.0 ml Propylene Glycol  5.0 ml MDI Lupranate5143 32.0 ml

Example 5

A formulation according to Example 1 was carried out by pre-reactingLupranate 5143 and polyether diamine D-2000 in 400 ml of acetone. Theresulting solution was then added slowly to the remaining ingredients. Acloudy poly(urethane-urea) solution resulted.

Example 6

A formulation according to Example 1 was carried out, except that MEKwas replaced by an equal amount of acetone.

Example 7

A formulation according to Example 1 was carried out, except thatone-half of the ethylene glycol and one half of the propylene gloyolwere each replaced with a stoichiometrically equivalent amount ofpolyetherdiamine D-2000.

Example 8

A poly(urea-urethane) formulation prepared according to Example 1 wasevaluated for drug delivery potential using in vitro release testing(IVRT) with hydrocortisone medicament. FIG. 1 shows that a film formedfrom a single application of the formulation, allows hydrocortisone toreadily pass through it. This result demonstrates that thepoly(urea-urethane) film allows transport of medicaments.

Example 9

A poly(urea-urethane) formulation prepared according to Example 1 with ahydrocortisone medicament was painted on a membrane surface 2×, 5×, and10× in 5 minute intervals. The resulting films were evaluated using invitro release testing (IVRT). Results are shown in FIG. 2. The releaseof hydrocortisone is predictable and is inversely proportional to thenumber of applications (and hence film thickness). Thus the release rateof the drug can be controlled by film thickness. These results indicatethat the polymer film can incorporate an agent (drug) into its matrixand release it at a constant rate.

Example 10

Water vapor transmission testing was conducted on films cast from apoly(urea-urethane) formulation prepared according to Example 1. Testswere carried out in accordance with test method ASTM E 96/E 96M-05 asfollows: Aluminum cups were filled with water to within 19±6 mm of thetop, and the sample films were sealed across the cup mouth. Threereplicates of each specimen were run. The samples were placed in asealed chamber with a saturated solution of magnesium nitrate tomaintain a controlled humidity. The temperature and humidity wererecorded with a solid state sensor, and the cups were weighedperiodically (every three and four days, alternately) until a steadyrate for mass loss was observed. The average temperature over thetesting was approximately 23° C., and the average humidity in thechamber was 74%.

The permeance of the film samples was calculated from the mass lossrate, temperature, humidity, cup dimensions, and film thickness and aregiven in Table 1. The edge mask, still air resistance, and surfaceresistance corrections were applied to the raw values obtained. Thewater transmission rate was high enough that buoyancy correction is notnecessary. Results clearly indicate that the film allows the passage ofwater vapor sufficient to aid in wound healing.

TABLE 1 Water Vapor Transmission results for poly(urea-urethane) filmsamples. Sample Permeance (ng s⁻¹ m⁻² mmHG⁻¹) 1 864 2 667 3 892 4 851

Example 11

A poly(urea-urethane) formulation sample prepared according to Example 1was tested for systemic toxicity [acute, injection] in accordance withtest method ANSI/AAMI/ISO 10993-11; 3-day gross observations of toxicityin mouse after single IP injection of 70° C./24 hr saline and vegetableoil extracts; five albino naïve mice per extract, five mice per control.

Acceptance Criteria: The test article meets the USP requirements if noneof the animals treated with the test article extract show asignificantly greater biological reactivity than those treated with thecontrol.

Results: The test article met the requirements of the USP SystemicInjection test using the extracting media and conditions listed, as nosignificant biological reactivity was observed.

Example 12

A poly(urea-urethane) formulation sample prepared according to Example 1was tested for delayed hypersensitivity [sensitization] in accordancewith ANSI/AAMI/ISO 10993-10; The repeated patch method of Buehler wasused to determine dermal sensitization reaction, but was modified toinclude a longer induction exposure period. Ten test guinea pigs werepatched on shaved areas with the test article and five guinea pigs withthe negative control. The test article was dosed neat and similarpatches were prepared for the controls. Animals were wrapped with anelastic bandage secured with hypoallergenic tape. Bandages and patcheswere removed after at least six hr of exposure. At 24+/−2 hr [restperiod] the sites were assessed for erythema and edema. The procedurewas repeated at days 7 and 14 for at total of three inductions.Following a two-week rest period the animals were topically challengedwith the appropriate test or control articles. The challenge patcheswere removed after at least six hr of exposure. The dermal patch siteswere again observed for erythema and edema at 24 and 48 hr after patchremoval.

Acceptance Criteria: Test results are based on incidence and severity ofthe sensitization reaction. Any skin reaction scores received by thetest group that are greater than the scores received by the negativecontrol group are considered to represent significant sensitization

Results: No adverse reactions were observed over the duration of thestudy and according to test criteria, there was no sensitizationpotential [0% incidence and 0% severity] of the test article for theanimals used in this study.

Example 13

A poly(urea-urethane) formulation sample prepared according to Example 1was tested for intracutaneous [Intradermal] Reactivity [irritation] inaccordance with ANSI/AAMI/ISO 10993-10: dermal irritation potential wasdetermined by applying 0.5 ml of the neat test article or negativecontrol [tap water] to the shaved skin of the dorsal area of threealbino rabbits for at least four hr. Observations for skin irritation[erythema, edema, necrosis] were done at one, 24, 48, and 72 hr afterunwrapping, using diluted alcohol to lightly swab the skin.

Acceptance Criteria: The requirements of the test are met if thedifference between the test sample and the vehicle blank score is 1.0 orless for all animals

Results: The requirements for the stated test were met. There was nosignificant dermal reaction observed at the test or control sites at anyobservation period for any animal [score=0].

Example 14

A poly(urea-urethane) formulation sample prepared according to Example 1was tested for cytotoxicity using an ISO elution test [MEM extract] inaccordance with USP 87 and ANSI/AAMI/ISO 10993-5; cell culture mediumelution method on slightly subconfluent mouse L-929 cells. Three testsand one control were made with 37° C./24 hr extracts. Reactivity andcytotoxicity were determined after 48 hr of incubation of the extractswith the cells.

Acceptance Criteria: Conditions of cell cultures are interpretedaccording to a cytotoxicity scale according to criteria in ANSI/AAMI/ISO10993-5. Samples are considered non-cytotoxic if the condition of thecell cultures indicates no cell lysis and discrete intracytoplasmicgranules.

Results: The test article showed no to slight cytoxicity according tothe scoring criteria in ISO 10993 in this sensitive, direct-contacttest.

Example 15

A poly(urea-urethane) formulation sample prepared according to Example 1was tested for cytotoxicity using an Agar overlay test: This testevaluates the cytotoxicity of diffusible components from materials orsolutions on mouse embryo fibroblast monolayers [L929 cells]. An agarlayer is added over slightly subconfluent confluent cell monolayers toprotect cells from mechanical damage. The sample is applied to sterilefilter paper discs; four discs were placed directly on the agar layerand the cells were incubated for 24 hr.

Acceptance Criteria: The test sample meet USP requirements if none ofthe cell culture exposed to the sample shows greater than a mildreactivity [grade 2].

Results: Following incubation, the cells were evaluated microscopicallyusing the grading evaluation criteria stated in the report. All resultsindicated a grade of “2” [borderline failure].

Example 16

A poly(urea-urethane) formulation sample prepared according to Example 1was tested for genotoxicity using a Chromosome Aberration Test: ChineseHamster Ovary cells were treated with saline and PEG extracts of theproduct film [37 C for 72 hr] in the presence and absence of S9metabolic activation, which is used to screen for mutagens frombyproducts of the sample. ‘Activated’ cells were exposed to test andcontrol extracts for 3 to 4 hr; Non-activated cells were exposed to testand control extracts for 16 to 18 hr. Before harvest, cells wereexamined for cytotoxicity. Cells were then harvested, fixed, stainedwith Giemsa, coverslipped and examined microscopically for chromosomeaberrations. All tests were in triplicate.

Acceptance Criteria: cytotoxicity is scored on a scale of 0 to 4 andnumber and types of various chromosome aberrations are scored forpositive and negative controls and the test extracts, which must bewithin ranges showed by the negative controls to be considerednon-genotoxic

Results: There were no cytotoxic effects of the test extracts under anycondition; polyploid, endoduplication rate and mitotic index in thetreated samples were the same as the negative controls, indicating thatthe product is not genotoxic.

Example 17

A sample prepared according to Example 1 was tested mutagenicity with invitro mouse lymphoma cells: Saline and polyethylene glycol extracts [37C for 72 hr] were made of 72 cm² of the polymer films and were used totreat indicator cells per ISO 10993:3. Again the S9 activation systemwas used to screen for mutagens from byproducts of the test sample.Negative and positive controls are run concurrently with the testarticle to provide ranges of spontaneous and inducible mutantfrequencies.

Acceptance Criteria: the assay must first be determined valid withnegative and positive controls over the assay range before determinationof mutant frequencies and cloning efficiency.

Results: saline and PEG controls performed as required, validating theassay with these extracts, which produced results well within the rangeof the negative controls, indicating that the product is not mutagenic.Saline and polyethylene glycol extracts were made of 72 cm² of thepolymer films and were used to treat the indicator organism[Salmonella]. Again the S9 activation system was used to screen formutagens from byproducts of the test sample

Acceptance Criteria: for a mutagen, a two-fold increase in the number ofrevertants compared to the negative control

Results: the extracts did not produce a two-fold increase in the numberof revertants in any of the 5 test strains and spot tests showed no zoneof reversion or of toxicity, indicating that the product is notmutagenic.

Example 18

A formulation according to Example 1 was applied to fire ant bites on asubjects hands and feet. Intiching subsided almost immediately.

Example 19

A formulation according to Example 1 was applied to spider bites andimmediately the itching and burning subsided. No additional harmfuleffects from the bite were observed.

Example 20

A formulation according to Example 1 was applied to the arms of a subectwith extensive dermatitis from poison ivy. After an brief burning, thepain, itching and swelling subsided.

Example 21

A formulation according to Example 1 was applied to a deep 2″ cut on thepalm of a subjects hand. The wound was held closed for approximately 30seconds by which time the formulation had dried and cured, holding thewound closed and stopping bleeding. The associated pain and throbbingsubsided.

Example 22

A formulation according to Example 1 was applied to a severe abrasion ona subject's knee. After a very brief period of stinging, the painsubsided, the bleeding stopped and the resulting polymer film formed aprotective bandage over the damaged skin.

Example 23

A formulation according to Example 1 was applied to a rash resultingfrom psoriasis. Itching and burning subsided and the resulting polymerfilm formed a protective film over the rash.

Example 24

A formulation according to Example 1 was applied to a herpes soreproviding relief from itching and burning and providing a protectivebarrier over the blisters.

Example 25

A formulation according to Example 1 was applied to rash resulting frompityriasis rosea. The itching and redness subsided and the resultingpolymer film formed a protective coating over the rash.

Example 26

A formulation according to Example 1 was applied to a sever sunburn ofthe scalp. Pain and discomfort subsided and the polymer film formed aprotective coating over the burned skin.

Example 27

A formulation according to Example 1 was applied to a burn on a subjectshand. The pain and swelling subsided and the polymer film provided aprotective coating over the damaged skin.

Example 28

A formulation according to Example 1 was applied to surgical stitchesand formed a protective coating.

Having thus described certain embodiments of the present invention, itis to be understood that the invention defined by the appended claims isnot to be limited by particular details set forth in the abovedescription as many apparent variations thereof are possible withoutdeparting from the spirit or scope thereof as hereinafter claimed. Thefollowing claims are provided to ensure that the present applicationmeets all statutory requirements as a priority application in alljurisdictions and shall not be construed as setting forth the full scopeof the present invention.

1. A method of treating a skin ailment comprising administering to asubject in need thereof, a therapeutically effective amount of acomposition comprising topically applying the composition comprising (i)a primary polyamine; (ii) a secondary aromatic polyamine; (iii) apolyisocyanate; and (iv) optionally, a polyol, wherein the skin ailmentcomprises at least one of the ailments selected from the groupconsisting of psoriasis, bites or stings, burns, sores, hemorrhoids,anal sphincter muscle tears, and cuts and scrapes, and wherein at leastone of the primary polyamine, the secondary aromatic polyamine and thepolyol reacts with the polyisocyanate to form a poly(urea-urethane)prepolymer.
 2. The method of claim 1, wherein the primary polyaminecomprises a polyether.
 3. (canceled)
 4. The method of claim 1, whereinthe primary polyamine comprises polyoxypropylenediamine.
 5. The methodof claim 1, wherein the secondary aromatic diamine comprisesN,N-dialkylaminodiphenylmethane or bis(sec-butylamino)diphenylmethane.6. The method of claim 1, wherein the polyisocyanate comprises at leastone of diphenymethanediisocyanate (MDI), a modified form of monomericMDI, MDI containing resin, aliphatic diisocyanates, aromaticdiisocyanates, alicyclic diisocyanates, ethylene diisocyanate,ethylidene diisocyanate, propylene diisocyanate, butylene diisocyanate,cyclopentylene-1,3-diisocyanate, cyclohexylene-1,4,diisocyanate,cyclohexylene-1,2-diisocyanate, 2,4-tolylene diisocyanate, 2,6-tolylenediisocyanate, 4,4′-diphenylmethane diisocyanate,2,2-diphenylpropane-4,4′-diisocyanate, p-phenylene diisocyanate,m-phenylene diisocyanate, xylylene diisocyanate, 1,4-naphthylenediisocyanate, 1,5-naphthylene diisocyanate, diphenyl-4,4′-diisocyanate,azobenzene-4,4′diisocyanate, diphenylsulfone-4,4′diisocyanate,dichlorohexamethylene diisocyanate, tetramethylene diisocyanate,pentamethylene diisocyanate, hexamethylene diisocyanate,1-chlorobenzene-2,4-diisocyanate, furfurylidene diisocyanate andtriphenylmethane triisocyanate.
 7. The method of claim 6, wherein thepolyisocyanate comprises MDI, a modified form of monomeric MDI and/or aMDI containing resin.
 8. The method of claim 1, wherein thepolyisocyanate comprises a carbodiimide modified MDI.
 9. The method ofclaim 1, wherein the polyol comprises at least one of ethylene glycol,propylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, 2,3-butyleneglycol, a propylene oxide adduct of trimethylol propane, polyethyleneglycol 200, polyethylene glycol 400 and polyethylene glycol
 600. 10. Themethod of claim 9, wherein the polyol comprises at least one of ethyleneglycol, propylene glycol and a propylene oxide adduct of trimethylolpropane.
 11. The method of claim 1, wherein composition furthercomprises a non-aqueous solvent selected from the group consisting ofacetone, methyl ethyl ketone, methylisobutylketone,N-methylcyclohexanone, acetaldehyde, propionaldehyde, butyraldehyde,isobutyraldehyde, methyl acetate, ethyl acetate, butyl acetate, andmethyl propyl acetate.
 12. The method of claim 11, wherein the volumeratio of the primary diamine in the composition ranges from about 3.6%to about 12.2% v/v, based on the total volume of the composition. 13.The method of claim 4, wherein the ratio of the primary diamine andsecondary aromatic diamine to the polyisocyanate in the composition isfrom about 2.8:1 to about 3.8:1 by volume.
 14. The method of claim 1,wherein the composition further comprises a colorant and/or pigment. 15.The method of claim 1, wherein the composition further comprises anantibacterial, antifungal and/or antiviral medicament. 16.-35.(canceled)